RTS,S/AS01E is the lead candidate pre-erythrocytic malaria vaccine. In Phase IIb field trials the safety profile was acceptable and the efficacy was 53% (95%CI 31%–72%) for protecting children against clinical malaria caused by P. falciparum. We studied CS-specific T cell responses in order to identify correlates of protection.

Methods and Findings

We used intracellular cytokine staining (for IL2, IFN?, and TNFa), ex-vivo ELISPOTs (IFN? and IL2) and IFN? cultured ELISPOT assays to characterize the CS-specific cellular responses in 407 children (5–17 months of age) in a phase IIb randomized controlled trial of RTS,S/AS01E (NCT00380393). RTS,S/ AS01E vaccinees had higher frequencies of CS-specific CD4+ T cells producing IFN?, TNFa or IL2 compared to control vaccinees. In a multivariable analysis TNFa+ CD4+ T cells were independently associated with a reduced risk for clinical malaria among RTS,S/AS01E vaccinees (HR?=?0.64, 95%CI 0.49–0.86, p?=?0.002). There was a non-significant tendency towards reduced risk among control vaccinees (HR?=?0.80, 95%CI 0.62–1.03, p?=?0.084), albeit with lower CS-specific T cell frequencies and higher rates of clinical malaria. When data from both RTS,S/AS01E vaccinees and control vaccinees were combined (with adjusting for vaccination group), the HR was 0.74 (95%CI 0.62–0.89, p?=?0.001). After a Bonferroni correction for multiple comparisons (n-18), the finding was still significant at p?=?0.018. There was no significant correlation between cultured or ex vivo ELISPOT data and protection from clinical malaria. The combination of TNFa+ CD4+ T cells and anti-CS antibody statistically accounted for the protective effect of vaccination in a Cox regression model.

Conclusions

RTS,S/AS01E induces CS-specific Th1 T cell responses in young children living in a malaria endemic area. The combination of anti-CS antibody concentrations titers and CS-specific TNFa+ CD4+ T cells could account for the level of protection conferred by RTS,S/AS01E. The correlation between CS-specific TNFa+ CD4+ T cells and protection needs confirmation in other datasets.